Proteins Crossing Membranes

A Scientist's Memoir

Stephen Rothman

• Publisher: CRC Press
• Year: 2019
• ISBN:
  9780429665189
• Edition: 1
• Topic: Politics & International Relations
• Subtopic: Politics
• Index: Politics & International Relations

In an intriguing series of experiments carried out many years ago, a common scientific belief, feted by no less than three Nobel prizes, was brought into question. The observations were about proteins—the molecules that the genetic code specifies and that are in one way or another central to all of life's activities. The experiments however were not about what proteins do, but how they are moved, in particular how they are moved from where they are made to where they act. The results of these studies conflicted with the standard view of how this happens, and thus became controversial.

The standard view, the vesicle theory of protein secretion, envisions proteins being carried within and out of cells en masse in membrane-bound sacs or vesicles. The controversial experiments demonstrated that to the contrary individual protein molecules cross the relevant membranes as a result of their own motion. This was thought to be impossible at the time. Proteins Crossing Membranes is a personal narrative that tells the story of the controversy. Among other things, the author illustrates that scientists, like the rest of us, can rigidly hold onto their beliefs despite evidence that they are misguided.

Key Features

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• Reviews the data in support and critical of the vesicle theory of protein secretion
• Explores the ways scientists respond to evidence that challenges a favored theory
• Documents the author's personal experiences in this conflict-laden situation

section three

Nature’s way

chapter thirteen

Testing the theory

Testing the already known

Falsehood flies, and truth comes limping after it, so that when men come to be undeceived, it is too late; the jest is over, and the tale hath had its effect.

Jonathan Swift

The Art of Political Lying, The Examiner, #14, 1710

As a young scientist trying to make sense of the vesicle theory, of what was believed and why, I found that the flimsiness of the evidence supporting the theory was not accompanied by uncertainty about its authority, but to the contrary by enormous confidence in it. And this was not merely the attitude of those who developed the theory, but the whole field of cell biology.

As best I could figure out, there were three reasons for this. First and foremost, there was faith in the appropriateness of the assumptions we have been discussing. Second, there was trust in the say-so and expertise of the scientists who carried out the research. And finally, there was a kind of breathlessness at the sophistication of their methods. I found each of these troubling. I was also disturbed by the unpleasant suspicion that some of the evidence was specious, that it had been selected, manipulated, or misrepresented.

Surely, I thought, science was not about some sort of categorical acceptance of a particular set of beliefs, akin to the faith of a religion. It was about questioning belief, not submission to it. Indeed, it seemed to me that this was what it meant to be a scientist. As a matter of intellectual and professional pride, scientists would bend their beliefs to accommodate nature’s facts. After all, they would say, theories are just theories.

As I began to question the vesicle theory in public and in print, I learned just how mistaken I was. My view of science and its purveyors was an idealization, a fairytale. I was utterly unaware of how passionate and fierce belief in scientific theories can be, how unyielding and uncompromising. I soon found out that one could not question the vesicle theory without the questioner, not just the question, being attacked. Both to my face and behind my back, with overt, shouted hostility, or soft, cunning snideness reeking of intellectual sophistication, I was variously called disagreeable, offensive, uninformed, ignorant, noncomprehending, obsessed, and finally unhinged.

I was completely unprepared for the barrage. Naïve and oblivious, I was in a haze of idealistic self-delusion. As the theory failed various tests, I credulously expected others to join me in questioning its notions. Not only didn’t this happen, there was no accommodation whatsoever. What I thought was convincing evidence against the theory was not met with excitement or at least interest, but with anger, rejection, and derision. I found myself under attack for expressing doubt. What gall; what cheek; what chutzpah!

Even those who seemed to agree with me, who saw the weaknesses and understood that our observations presented a real challenge to the theory, usually expressed their opinions under their breath, sometimes literally whispering in my ear. In public they were mute, cowed, or cowardly. From time to time, I was offered friendly advice. Why, they would ask, was I causing such a ruckus? What was the point? Attitudes were not going to change. I was not going to convince anyone. Do something else with your time!

Over the years, the vesicle theory failed dozens of tests in our hands. Sadly, however undeniable the results, and whether they came from one test or many, they failed abysmally to pierce the armor of a world that seemed to be populated by closed or fearful minds. At the time, I wondered whether this was my fault. After all, I was young and inexperienced. Maybe there was a proper way to question a theory, with a certain delicacy and sensitivity, whose refinements I had not yet learned. Certainly, the attacks on me were not sugarcoated.

At any rate, whatever the cogency of our experiments, however gripping the results and whatever the combined impact, they were greeted with anger, rejection, and derision, by fear and cowardice and by committed attempts explain them away. It was said that our technique was faulty, that our results were artifacts of one sort or another, and if neither criticism sufficed, then our observations were most certainly properly explained (more like explained away) in a fashion that was agreeable to the vesicle theory. It accounted for what we saw, our claims to the contrary notwithstanding.

Even if all this failed, the unnerving results could always be ignored, put out of one’s mind, out of the collective mind of the field. Just written off. They were simply not worthy of note. In any event, our whole body of work was either spurned or disregarded. It had no serious impact on the beliefs and attitudes of cell biologists. Still, these wonderful experiments shaped my scientific odyssey. Benighted or not, they are at the heart of this book. We will get to them in a minute, but before we do, we need to make one final preparative diversion.

To understand why things happened the way they did, to understand why our studies were treated so dismissively, we have to talk a bit more about the scientific method. I raised its great shadow in the Praeludium as well as from place to place in the discussion to this point. This may elicit yawns of boredom from some of you. Get on with it! But this is no mere scholastic exercise. Having a sense of science’s method is critical to any consideration of our experiments and the subject more generally, not to mention scientific knowledge more broadly. What was our purpose, our scientific purpose, in performing the experiments? What were we after? And what were the motives of those who greeted them so contemptuously?

To answer these questions, we have to look beyond the attitudes of the individuals involved in the dispute to the views of the 20th century’s two most influential thinkers about the nature of science, the philosopher Karl Popper and the social commentator, historian, and physicist Thomas Kuhn. Two schools of thought emerged from their ideas, not surprisingly called “Popperian” and “Kuhnian.” Their apostles have in one way or another been at each other’s throats for decades because their perspectives have been thought to provide opposing views of science.

I did not think so. In my mind, the two schools of thought were perfectly compatible. They just focused on different aspects of the same activity. They seemed to be arguing past each other. Popper was concerned with the theory of science and Kuhn with its practice. Of course, both must be taken into account in any attempt to explain the enterprise.

My intentions in carrying out the experiments (I shall discuss some of them in the following chapters) are found in Popper’s point of view and the motivations of my adversaries’ in Kuhn’s. Befitting a philosopher, Popper understood science in formal terms. He said that true science had two characteristic features: deductive tests of theories and the rule of falsification. The proper scientist, as opposed to the mere researcher, formulated hypotheses deduced from some general theory as a means of testing that theory’s soundness. Does nature behave as the hypothesis, and hence the overarching theory predict? If it does, and if such and such should happen and it does, we say that the theory is affirmed, shown to be correct. If does not, then the hypothesis is false and by extension so is the larger theory from which it is derived.

Popper tells us that if we cannot devise deductive tests of a theory, then it is not a scientific theory, however sophisticated it may seem otherwise. The reason is simple. If we are unable to test our theories, then we have no way of knowing whether or not they are true or false, correct or incorrect. All we have, all we can have are prejudices, our own biased counsel to guide us in the search for the truth.

Popper’s second principle, the principle of falsification, conveys the depressing news that all science can truly, that is, unambiguously know about nature is what is not true, what is false. Tests that affirm our theories, that suggest that they are correct, and that thereby give them credence, necessarily leave their actual truth or falsity eternally contingent. However seemingly incontrovertible and however numerous the affirmations, scientific theories are by their very nature always vulnerable to being proven false by the next test.

Hard-won scientific understanding does not become self-evident at some point, beyond question, as a result of experimental or theoretical success. Doubt is always and forever legitimate. Not only that, but to be genuinely dedicated to science, to truly be a scientist, the investigator must try to show that scientific ideas, theories and models that are thought to be true, including his or her own, are false. Only ideas that are exposed time and again to the fire of doubt, to tests that may show that they are false, but have survived the conflagration, have a legitimate claim to be descriptive of nature’s properties. In this process, skepticism is an act of the highest sort—the truest, most sincere, most faithful, and ultimately, the most insightful kind of scientific thinking.

Kuhn’s view was very different. Grounded in history, it was less a matter of theory than practice. It also had two elements. The first concerns what constitutes scientific belief and the second how that belief changes. According to Kuhn, at any given time, scientists in a particular field of study hold a fixed set of beliefs in common that save for relatively unimportant details are inclusive of all the properties, mechanisms, and processes known in that field of study. Kuhn called such belief systems “paradigms,” a term he borrowed from the social sciences and that has long since entered our everyday vocabulary. A paradigm is an exemplar or archetype. It is the way something is thought about, a set of beliefs.

Scientific paradigms embrace a multiplicity of things. Naturally they include theories, as well as the evidence and methods used to support and develop them. But in addition they include all sorts of suppositions, presumptions, and assumptions, supported and unsupported, substantiated and unsubstantiated, as well as prejudices and biases of all kinds, including lies. To this ungodly mess we must add the political and social context in which the beliefs are acquired and held. This includes the education of students, claims of authority, expressions of power and position, access to funds, as well as scientific misdeeds, such as the distortion and selection of data, even outright fabrication. All of it, from theory, to education, to evidence, to assumptions, to data selection and fabrication, to the power of authority, are devoted to one goal and one goal alone—promoting the perspective of the paradigm.

This takes us about as far away from Popper’s simple testable theory as possible. In the world of the paradigm, the mandates are wholly different. Scientists who labor within its borders, in what Kuhn calls “normal science,” seek evidence to strengthen it, to elucidate and clarify its claims, but, and this is critical, not to test or question them. Its constituent models are understood to be true in general, to provide a proper description of nature’s properties. At any given time, the paradigm is thought to provide their more or less complete characterization in the particular field of study. Whatever doubts and uncertainties remain are either inconsequential or solvable within the borders of the paradigm.

Kuhn believed that the great majority of scientists work in the world of normal science. Their task is to fill in gaps in knowledge, to determine what remains unknown or uncertain in a system that is thought to be true as a general matter. Their research is like striving to complete a jigsaw puzzle whose solution is known from the picture on the box top, except that in this case, the task is not to realize a picture, but to perfect the viewpoint of the paradigm.

Despite the alignment of powerful forces devoted to strengthen the paradigm, to make it permanent, Kuhn knew as a matter of history that there are no fixed beliefs in science. From time to time, indeed time and again paradigms are upended. And yet, he wondered, how could this happen? How could such a change take place if all the experts in an area held the same beliefs and were working assiduously toward their perfection?

Who would rebel, who would break the bond of allegiance? In other words, who would become a traitor to the common cause? Kuhn answered this question by introducing a kind of deus ex machina, someone from a different discipline, who, ignorant of the mandates and constraints of the belief system, “upsets the apple cart” and puts the paradigm in jeopardy with a new piece of evidence or a new theoretical insight. Whether intentional or not, the outsider introduces conflict into a pacific world of comfortable and shared understanding.

As Kuhn described it, when this happens, followers of the paradigm do not, as one might innocently expect (as I did), respond by accommodating their views to the new information. Instead, they rush headlong to the barricades to defend the status quo ante and do so with great ferocity. The challenge or challenger is deemed unworthy. The demurring scientist is dishonest, incompetent, and in any event, the paradigm can explain it all, or at least everything worth explaining, at least well enough. In response, the upstart may gather further evidence, posit further arguments, highlight previously obscure flaws in the paradigm, thereby instigating new attacks on the bastion. A battle for primacy ensues that Kuhn called a “scientific revolution.”

In this view, changes in scientific understanding do not occur gradually, a little bit at a time, a little here and a little there, as scientists slowly hone in on the truth of the matter as is often thought. This gradualist view of scientific progress dominated thinking for centuries and is credited to Francis Bacon in 16–17th century England. Kuhn disagreed wholeheartedly. Instead, he saw a cataclysm in which the old paradigm is toppled, and a new order, a new understanding, a new paradigm is installed. Popper’s agreeable experimental tests and deductive logic are not the change agents in the real world of science, in Kuhn’s world. Things there are not so pure or so rational. Belief in the old paradigm, in the old view, was not disinterested, but committed, colored by strong biases, and often by harsh, even rotten social and political forces both within and outside the academy.

As a young scientist, I was a committed Popperian, naive about the world of Kuhnian debauchery I was about to enter. In varying measure, humans share two opposite traits of character—skepticism and naivety. I was at one and the same time a skeptic about scientific knowledge and a naive Popperian. My skepticism was expressed in my belief in experimental test to assess the validity of theories, and my naivety in the belief that the results of such tests were the standard bearers of scientific progress. I was in an amiable Popperian reverie from which I was about to experience an abrupt awakening to the ugly Kuhnian world.

With these thoughts in mind, we are now ready to tell the story of Proteins Crossing Membranes. As I have explained, only with a veritable phalanx of preconceptions, did the experiments we have discussed provide validation of the vesicle theory. Most important among them was the understanding that all proteins made on ribosomes attached to the endoplasmic reticulum were excluded from the cytoplasm. Yet, and this was my driving motivation, against this deeply rooted mindset, with its many assumptions, presumptions, and suppositions, stood one simple fact—Despite assertions to the contrary, the actual properties of protein movement in the living cell were unknown!

What was thought was in great part ers...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Dedication Page
• Table of Contents
• Foreword
• Preface
• Acknowledgments
• Praeludium
• Section I: Intimations and forebodings
• Section II: On the versimilitude of simulacra
• Section III: Nature’s way
• Section IV: Reification and attitudes
• Notes and selected readings
• Index